Post-Menopausal Hormone Therapy and Alzheimer’s Prevention
The onset of menopause in middle-aged women increases the vulnerability of women to Alzheimer’s disease. This is likely associated with the reduced levels of estrogen in post-menopausal women.
The hormonal changes that take place during the menopausal transition and post-menopause have the potential to affect the processes concerned with cognition. But this cannot be assessed directly as menopause is not something that can be randomly allocated as an experimental intervention.
Facts Relating Estrogen Levels With Dementia:
According to an unpublished data from Chicago Health and Aging Project (CHAP), in US 2013 the number of women aged 65 and above with Alzheimer’s were 3.3 million compared to 2 million men.
Mood swings during the menopause transition, memory, and cognitive function also indicates the effect of low estrogen on brain actions.
What are Estrogens?
Estrogens are the hormones produced in women by the ovaries. The developing ovarian follicles produces estrogens and progesterone cyclically during the reproductive years of woman’s life.
On average about two years before the final menstrual period, the menstrual irregularity begins and the hormones levels fluctuate. This is the defining period of menopause during which the estrogens (beta-estradiol and estrone) levels reduces gradually reaching the lowest about two years after the last menstrual period.
After the menopause the estrogen levels in women is much lower than men. In these women androgen steroids hormone precursors produced from the theca cells of ovaries and the adrenal cortex convert to give estrogens.
Estrogens play an important role in the female reproductive cycle, but studies in animal and in vivo cell have suggested that these hormones can have beneficial cholinergic effects on structures of brain including those related to memory and learning such as the hippocampus and basal cholinergic forebrain (McEwen 1997). A consistent decrease in the cholinergic activity is noted in alzheimer’s patients.
Estrogen Levels May Affect Cognitive Function
Estrogen Appears to be Involved in a Variety of Mechanisms
- Anti-amyloidogenic effects
- Antioxidant effects
- Dendritic sprouting
- Effects on various neurotransmitters involved in cognitive function
In the mitochondria, estrogen receptors play an important role in protecting against oxidative stress which is one of the earliest events in Alzheimer’s pathogenesis.
The two types of classic intranuclear receptors for estrogen are estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). These receptors are expressed on glia and neurons in brain areas that are involved with cognitive function. Such areas include forebrain cholinergic neurons of the nucleus basalis (involved in memory and attention), neocortex and hippocampus(critical to memory encoding). (Taylor et al., 2009) (Ishunina and Swaab, 2009) (Shughrue et al., 2000) (González et al., 2007)
These receptors are encoded by different genes on separate chromosomes and a number of ERα and ERβ splice variants have been identified in human brain, which are area specific and whose expression may be modified by Alzheimer’s disease.
Hormone Replacement Therapy
It is a therapy given to women approaching menopause to replace the hormones that are at low levels. This is used to treat menopausal symptoms such as hot flashes and night sweats. Estrogen replacement therapy(ERT) is the treatment involving replacement with estrogens. It is widely used in the treatment of osteoporosis. Whereas, hormone replace therapy (HRT) is the combined therapy with estrogens and progesterone.
Maintaining high levels of oestrogens in postmenopausal women by means of ERT or HRT could possibly prove protective against development of Alzheimer’s or other dementia symptoms. Mot studies suggest the same. (Hogervorst 2000; Yaffe 1998a)
Studies Evaluating the Use of HRT for the Prevention of Alzheimer's Dementia
Most studies have found that oophorectomy (surgical menopause) prior to natural menopause increases the risk of cognitive decline and AD. Whilst conversely oophorectomy after natural menopause age which is around 51 years does not alter the risk of AD. This implies that the early loss of oestrogens can accelerate the development of dementia or AD. However, this relationship has been reported only for women older than 85 years.
The question arises that if depletion of sex steroid hormones at menopause is a risk factor for AD, then maintenance of these hormones would be predicted to reduce the risk AD development. Consistent with this idea, AD risk has been reported to be lowest in postmenopausal women with the highest endogenous Oestrogen levels and greatest in those with low Oestrogen levels.
Results of the Women's Health Initiative (WHI), indicated elevated risk of dementia rather than reduced compared to placebo group. In this study 4532 women with natural menopause were given conjugated equine estrogen (CEE) combined with MDPA comparing to placebo. However, due to an unexpected adverse risk the trial was discontinued.
Many factors may contribute to the discordance of estrogen’s benefits such as the combination of estrogen with progestin as in this case. The women studied in WHIMS trial are 65 years or older. So this study may or may not generalise to younger postmenopausal women and also to AD as it was not studied as a seperate endpoint in this trial.
The Timing of Hormone Therapy May Affect the Prevention of Alzheimer's
Critical window or Healthy cell hypothesis suggests that the initiation of HT near the onset of menopause is hypothesised to be important for its efficacy. This is similar to the fact that there is an increased risk of coronary heart disease when hormonal therapy is initiated in late menopause. While, there is no effect if HRT is initiated close to menopause.
As we have seen in the WHIMs trial, the mean age of women under study was 65 years which is 14 years past 51 years, the average age of menopause onset. Studies in which HRT was initiated at or near menopause showed cognitive benefits rather than risks.
In a Danish study of HRT for osteoporosis, midlife women were randomised to HRT and placebo groups. Cognitive benefits were observed in the follow-up of more than 10 years after the 2-3 years HRT regimen.
However, there is no clear connection between the age at the onset of menopause and Alzheimer risk or between natural menopause and memory loss.
Similarly in another study (MIRAGE) , a reduced risk of AD was observed with hormone therapy in younger women, but not older women.
The Confounding Issues
It is possible, though hypothetical, that some approaches of treatment such as different formulations, dosage forms (foe example, a transdermal patch or a pill) might lead to better cognitive outcomes than thus far achieved. It is also possible that compounds related to oestrogen but not estrogens such as selective estrogen receptor modulators could be effective where as estrogens are not.
Observational studies that suggests reduced AD risk with HRT are subject to bias (Barrett-Connor 1991). For instance, women who choose to use ERT or HRT after the menopause in general are more education, have healthier life-styles and are also healthier before using ERT or HRT compared to women who do not chose to use ERT or HRT (Matthews 1996). Healthier lifestyle can decrease the risk for dementia.
More work will be required to clarify the link between HRT and AD risk. However, the emerging reports seem to suggest that short term HRT near menopause onset may offer a reasonable strategy to hinder the development of dementia at later stages of life.
A total of six drugs have been approved by the FDA to address the symptoms of Alzheimer’s dementia. However, none of these drugs stops or slows the progression of AD. Also, toxicity and adverse effects can occur with the long term use of these agents. Hence, the interest toward hormone therapy has been increased.
Although, the human research studies did not demonstrate convincing roles of estrogen and related compounds in the treatment or prevention of AD, but these studies suggest research opportunities.
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